Vol. $4, No. 4, April 1969
ARYL(TRICHLOROMETHY L) CARBINOLS 1005
Reaction of Cyanamide with Aryl(trichloromethy1)carbinols. A Novel Synthesis of Alkyl 5-Aryl-2-imino-4-oxo-l-imidazolidinecarboximidates WILKINSREEVEAND EUGENE BARRON' Chemistry Department, University of Maryland, College Park, Maryland 907& Received August 8,1968 The reaction of cyanamide with aryl(trichloromethy1)carbinols in alcoholic potassium hydroxide unexpectedly formed alkyl 5-aryl-2imino-4-oxo-l-imidasolidinecarboximidates(l),in yields as high as 61 %. Several reactions of these compounds are discussed. They can be hydrolyzed with acid to alkyl l-aryl-2,4dioxo-l-imida~olidinecarboxylates (3 j, and with base to either arylhydantoic acids or to a-aminoarylacetic acids depending upon the severity of the reaction conditions.
Aryl(trichloromethy1)carbinols are useful intermediates for the synthesis of several interesting series of compounds. Phenyl(trichloromethy1)carbinol reacts with methanolic or ethanolic potassium hydroxide to form a-alkoxyphenylacetic acids12 with potassium amide in liquid ammonia to form a-aminophenylacetic acid13and with thiourea to form 2-imino-5-phenyl-4thia~olidinone.~ I n the present work it was desired to study the reaction of various aryl(trjchloromethy1) carbinols with cyanamide in alcoholic potassium hydroxide. Unexpectedly, this reaction led to a novel synthesis of alkyl 5aryl-2-imino-4-oxo-l-imidazolidinecarboximidates (1) , the preparation of which has not previously been described. This paper reports both the synthesis of these compounds and several of their reactions used in structural elucidation. Synthesis.-The preferred conditions for preparing compounds la-f involved adding an alcoholic potassium hydroxide solution to the aryl(trichloromethy1)carbinol and cyanamide in alcohol at 0" and finally warming the reaction mixture to 40" (Scheme I). Under these conditions, aryl(trichloromethy1)carbinols are postulated to form unstable dichloro epoxides as
cyanamide anion is believed to attack the epoxide to give first a substituted acyl chloride which in turn is attacked by a second anion of cyanamide. Subsequent cyclization and formation of an imino ether lead to the reaction product (1). Apparently the ring closure occurs in the strongly alkaline reaction medium, rather than during the neutralization step, because small amounts of 1 were found in the ethereal extracts of the strongly alkaline reaction mixture. The possibility that cyanamide first dimerizes to dicyandiamide and that the latter is the intermediate which reacts with the phenyl(trichloromethy1)carbinol can be eliminated; compound la is obtained in only 6% yield from the reaction of phenyl(trich1oromethyl)carbinol and dicyandiamide under the usual reaction conditions. Compounds la, lb, and IC were formed in yields of 56, 61, and 28%, respectively, using ethyl alcohol as the solvent. The reduced yield with IC is apparently due to nucleophilic attack on the epoxide ring being inhibited by the electron-donating p-methoxy group. With methyl, n-propyl, and n-butyl alcohols a=ssolvents, compounds Id, le, and If were formed in yields of 22, 38, and 38%, respectively. A competing reaction is
SCHEME I
.-
la, R = Et; X = H b, R = Et; X = C1 c, R = Et; X = Me0 d , R = Me; X = H e, R = n-Pr; X = H f , R = n-Bu; X = H
intermediates.2 Accordingly, in the reaction of the aryl(trichloromethy1)carbinols with cyanamide, the (1) National Science Foundation Cooperative Graduate Fellow, 196E1967; abstracted in part from the doctoral thesis of E. Barron, University of Maryland, 1967. (2) Consult W. Reeve and C. W. Woods [ J . Amer. Chem. Sac., 81, 4062 (1960) ] for leading references. (3) W. Reeve and L. W. Fine, J . Org. Chem., PO, 1148 (1964). (4) W. Reeve and M. Nees, J . Amer. Chem. Sac., 89, 647 (1967).
the attack of the alkoxide ion on the postulated epoxide leading to the formation of an cy-alkoxyarylacetic acid;2 for instance, in the case of la this accounted for 20% of the carbinol consumed, potassiumhydroxide in mol was superior to sodium ethoxide in anhydrous ethan01 in SrJiteof the fact the more anhydrous conditions are knoGn to favor imino ether formation. Structural Studies.-Proof of the structure assigned
The Journal of Organic Chemistry
1006 REEVEAXD BARROX to compound la follows from analytical data (the molecular formula is CI2Hl4N4O2), spectral data, certain reactions, and conversion of la into a known derivative of a related compound. la, only slightly soluble in common organic solvents, is soluble in dimethyl sulfoxide and in trifluoroacetic acid. The nmr spectra in these solvents clearly showed the presence of an ethyl group, the phenyl ring, the proton on carbon five, and suggested the presence of three protons on nitrogen. I n trifluoroacetic acid, compound l a was converted into 5-phenylhydantoin. The above does not establish the position of the ethoxycarbimidoyl group. The two cyanamide moieties could add to each other to give the ethoxycarbimidoyl group substituted at either positions 1 or 3. Proof that it is in the 1 position follows from a study of compound 2a, obtained by refluxing l a with 20% sulfuric acid (Scheme 11). Compound 2a is
recorded on a Varian A-6@ with tetramethylsilane as the internal standard; when dimethyl sulfoxide was used as the solvent, the solvent peak a t 6 2.62 was used as the reference. Analyses are by Dr. Franz J. Kasler. General Procedure for the Preparation of 1. Ethyl 2-Imin0-4oxo-5-phenyl-1-imidazolidinecarboxhidate (la).-To a stirred solution of 22.5 g (0.1 mol) of phenyl(trichloromethy1)carbinol and 10 g (0.24 mol) of cyanamide in 50 ml of absolute ethanol maintained a t 1-4', there was added over a period of 1 hr a solution prepared by dissolving 33 g of potassium hydroxide pellets in 200 ml of absolute ethanol. The reaction mixture was allowed to warm gradually to room temperature while being stirred overnight, and was then warmed to 40' for 1 hr. After the potassium chloride was filtered off and an equal volume of cold water had been added to the filtrate, the filtrate was cooled to 10' and adjusted to a pH of 7.5. The mixture was allowed to stand for 1 hr a t -5O, and the precipitate was then filtered and washed with water and ethanol. The crude material melted with decomposition a t 200-202' and weighed 13.6 g (56% of theory). One recrystallization from 1800 ml of 95% ethanol gave 11.4 g: mp 204-206' dec; ir 3300-3250, 3000, 1720, 1660,
SCHEME I1
2a
1N
3
4
reflux.
PhCHCOOH
I
NHOONHZ
2"
soluble in dilute base as are 1-substituted hyantoins (but not 3-substituted hydantoins), and the NH signal in the nmr spectrum (dimethyl sulfoxide solvent) occurs at 6 11.4 typical of an N-H bond at the 3 position (a proton a t the 1 position gives a signal at 6 7.9-9.3).5 Finally, methylation of compound 2a gave an N-methyl derivative (3) which on hydrolysis with dilute sodium hydroxide gave the known 3-methyl-&phenylhydantoin (4). Compound l a may also be converted into phenylhydantoic acid and into phenylglycine by refluxing with dilute and concentrated sodium hydroxide solutions, respectively. A number of tautomeric structures are possible for compound 1. The low solubility of this series of compounds in common organic solvents suggests a zwitterionic structure, especially since the compounds of the 2 series are readily soluble in these solvents. Furthermore, the two broad singlets occuring in the nmr spectrum around 6 9.5 and 9.0 are characteristic of a positively charged imino group.4 Experimental Section All melting and boiling points are corrected. The decomposition points given, particularly for the imino carboximidates, were determined by placing the capillary melting point tubes in the melting point bath 10' below the decomposition point while the bath temperature was rising 2'/min. The ir spectra were recorded on a Perkin-Elmer Model 337 spectrophotometer. Halocarbon oil mulls were used for the region 4000-1350 cm-l; Nujol mulls from 1350 to 500 cm-l. The nmr spectra were (5) R. -4. Corral and 0.0.Oraei, Spectrochim. Acta, 31,2119 (1965).
1460, 1340, 1270, 1150, 1120, 1095, 890-810, 770, 750, 710, 695, and 630 crn-l; nmr (DMSO) 6 9.5 and 9.0 (broad singlets, 1 and 1, N protons), 7.4 (partially split singlet, 6, C& plus an =NH under the phenyl peak), 5.23 (s, 1, -CH
